The purpose of this project is to ascertain the possible involvement of metalloproteinases (MP) of the retina/choroid in a number of prevalent, blinding retinal diseases, particularly those involving abnormal cellular migration and neovascularization, and their function in normal turnover of components of the interphoreceptor matrix (IPM). Age-related macular degeneration, proliferative vitreoretinopathy and proliferative diabetic retinopathy together account for most of the new cases of blindness in developed countries each year. Proliferation of abnormal cells and neovascularization are involved in all of these diseases. The cells primarily affected maintain contact with each other through the IPM. Since this is an enclosed space, a localized method must be available for turnover of its components. The MPs found in the IPM may play an important role in this process. However, MPs have also been implicated in pathological states, including breakdown of basement membranes, neovascularization, cellular migration and proliferation. Does maintenance of normal retinal homeostasis require proper balance of MPs and their inhibitors within the IPM as in other extracellular matrices? When this balance is disturbed, do changes occur within this matrix which are involved in serious retinal diseases? The long-range goals of this research are to determine the function of the MPs in the IPM, to elucidate the mechanism whereby their activity is normally regulated and to ascertain their involvement in retinal diseases. To achieve these goals we propose to begin with studies designed to achieve the following specific aims: [1] Characterize the MPs in bovine IPM, [2] Characterize the MP inhibitors in bovine IPM, [3] Elucidate the regulation of MP activity. This system will be studied as follows: [1] Western blots will be screened with antibodies to known MPs and MP inhibitors to detect unique forms. If present, these forms will be purified and their composition, activation pathway, and exogenous substrates are among the properties which will be studied. [2] Endogenous substrate specificity will be determined for all MPs present, using labeled substrates and gel electrophoretic separations. [3] Specificity of the inhibitors will be determined by measuring their effect on enzyme activity and their binding to enzyme. [4] Cell(s) responsible for the synthesis of these materials and the effect of growth factors on their secretion will be studied on cells grown in culture. This project should lay the foundation for future investigations of this system in human tissue and for potential treatment for these devastating retinal diseases.